Treatment of gastritis using dimethylpolysiloxane

ABSTRACT

Dimethylpolysiloxane is effective for the treatment of gastritis.

This is a Rule 60 Divisional of Ser. No. 07/528,078 filed May 24, 1990,now U.S. Pat. No. 5,120,533.

DESCRIPTION

The defoaming effect of dimethylpolysiloxane is well investigated and isalready used therapeutically as antiflatulent or in preparation forsonography.

It has been found, surprisingly, that dimethylpolysiloxane can beemployed with a particularly advantageous effect for the treatment ofulcerous disorders of the gastrointestinal tract. The defoaming effectof dimethylpolysiloxane is correlated with the other physicochemicalproperties film-formation and adhesion to walls. It has emerged,surprisingly, that dimethylpolysiloxane can also be administered orallyover extended periods without disadvantageous effects in order to formand maintain in the oesophagus and in the gastrointestinal tract ofhumans a protective layer which assists the healing process whendisorders of the type described are present.

The agent according to the invention is particularly employed for thetreatment of ulcerous disorders of the gastrointestinal tract, generallyof disorders of the oesophagus, of the stomach and upper smallintestine, such as oesophagitis, ulcers (gastric and duodenal). It isused in the form of an orally administerable composition with apharmaceutically acceptable diluent or carrier, e.g. in the form ofchewable tablets.

The use according to the invention of dimethylpolysiloxane experiencesan increase in its effectiveness when the agent is taken in conjunctionwith silica gel.

This results in the coating which is generated by the agent in theoesophagus and gastrointestinal tract having a gel-like structure. Thislayer comes very close to the physiological mucus (e.g. gastric mucus)which protects the mucous membranes of the oesophagus andgastrointestinal tract.

It is possible with the agent employed according to the inventionspecifically to coat the mucous membranes of oesophagus andgastrointestinal tract over a prolonged period by appropriate intakeeven for days, weeks or months, and thus protect them against theaggressive constituents of the gastrointestinal tract, such ashydrochloric acid and digestive enzymes. The protection brought about bythe agent employed according to the invention effects, on the one hand,a reduction in the activity of tissue-damaging mechanisms and, on theother hand, a comparatively unimpaired regeneration of the wallsassociated with the cell regeneration and with the ulcer cleansing. Theagent employed according to the invention additionally brings about anincrease in the pH (buffering of raised acid values) in the stomach. Thesubjective feeling of the patient improves due to intake of the agent,the `heartburn` of the frequently hyperacid patients disappears.

INVESTIGATIONS

The following were investigated as a function of the dose and time:

1. Distribution and film-formation of dimethylpolysiloxane in thestomach.

2. Distribution and film-formation of dimethylpolysiloxane in theduodenum.

8 healthy men aged 25 and 40 years were employed as volunteer subjects(Table 1). The study was carried out as a controlled, randomized phase Istudy in crossover design. For the crossover design, the 8 subjects werereandomized and assigned to the two dosage forms. The investigationswere carried out at an interval of 7 days.

Two dosages were used per subject in the crossover design:

Dosage 1: 80 mg of dimethylpolysiloxane: (2×40 mg dimethylpolysiloxanechewable tablets)

Dosage 2: 160 mg of dimethylpolysiloxane: (4×40 mg dimethylpolysiloxanechewable tablets)

The composition of the dimethylpolysiloxane chewable tablets is shown inTable 8.

No other drugs were allowed to be taken immediately before and duringthe study. Furthermore, smoking was not permitted on the day of theinvestigation.

CONTROL INVESTIGATIONS

A comprehensive history was taken at the initial investigation; inaddition the basic physical and neurological investigations. Laboratorytests were also carried out.

The following gastroenterological progress investigations were carriedout on all the subjects on both investigation days:

1. Gastroscopy with documentation of oesophagus, stomach and duodenumimmediately before chewing the dimethylpolysiloxane tablets.

2. The same investigations, including the documentation, 30 minutesafter taking the chewable tablets.

3. The same investigations, including the documentation, 2 hours afterchewing the dimethylpolysiloxane chewable tablets.

The investigations were carried out twice for each subject, with eachalternative dosage, at an interval of 7 days. At a second progressinvestigation, in addition the pH of the stomach contents was measuredat each gastroscopy.

The subjects were not allowed to take any food or drink for at least 6hours before each drug intake and gastroscopy.

To prepare for the endoscopy, each subject received 0.5 mg of atropinein 1 ml of NACL solution administered subcutaneously. The localanaesthetic given for the mouth and pharyngeal space was WanderNovescine 1% solution (oxybuprocaine-HCL).

The gastroscopic investigations were carried out with an Olympus typeP₁₀ instrument. Documentation was effected by the visual findings andphotography.

RESULTS 1. Change in the Stomach pH

Table 2 summarizes the changes in pH based on the pH at theinvestigation immediately before medication and 2 hours aftermedication.

The dimethylpolysiloxane administration leads to a distinct increase inthe pH, i.e. a distinct shift from strongly acid in the direction of thealkaline range, irrespective of the number of chewable tabletsadminstered. Despite the small number of subjects, this difference issignificant at the 5% level.

Subject 7 was removed from the calculation because he had a duodenal capgreatly deformed by scarring and, moreover, the pH was already near thealkaline range (pH 6.05 or 6.83).

2. Film Formation

Table 3 summarizes the individual results in Tables 4 to 7. The aim ofthe study was to demonstrate that the dimethylpolysiloxane remained inthe stomach or duodenum in the observed period of 2 hours afteradministration of chewable tablets. The results are unambiguous.Administration of only 2 tablets of dimethylpolysiloxane (80 mg) leadsto a reaction in all the subjects. This is even more evident due toadministration of 4 tablets of dimethylpolysiloxane (160 mg).

At 360 mg, a relatively large amount of milky secretion was evident asobservation parameter on the gastric mucous membrane in 7 of 8 subjects.

The individual findings (and the summary findings) are set out in Tables4 to 7.

Evaluation of the visual findings and of the photographic documentationallows the summary assessment to be made that dimethylpolysiloxanechewable tablets and dimethylpolysiloxane are able to form an adhesivefilm on the gastric mucous membrane and in the proximal part of theduodenum.

                  TABLE 1                                                         ______________________________________                                        Anamnestic data on the subjects in the dimethylpolysiloxane study                        Mean  SD     Min    Max  Median                                    ______________________________________                                        Age          32.15   4.51   25   40   31.5 years                              Weight       179.75  7.31   170  191  181  cm                                 Weight       78      7.68   63   90   77   kg                                 Systol. blood pressure                                                                     116     9.99   101  130  114.5                                                                              mmHg                               Diast. blood pressure                                                                      78.62   8.44   62   90   81   mmHg                               Pulse        63.5    10.94  53   88   60.5 /min                               ______________________________________                                    

                  TABLE 8                                                         ______________________________________                                        40 mg dimethylpolysiloxane chewable tablets                                   Composition per tablet:                                                       ______________________________________                                        I.    1)   Dimethylpolysiloxane DAB9                                                                             40.000 mg                                        2)   Highly disperse silica DAB9                                                                           12.555 mg                                        3)   Peppermint oil DAB9     0.300 mg                                              Aniseed oil DAB9        0.033 mg                                         4)   Microcrystalline cellulose DAB9                                                                       200.000 mg                                 II.   5)   Mannitol DAB9           338.111 mg                                       6)   Saccharin sodium DAB9   0.667 mg                                         7)   Carboxymethylcellulose sodium DAB9                                                                    1.667 mg                                   III.  9)   Magnesium stearate DAB9 3.333 mg                                        10)   Maize starch DAB9       3.333 mg                                   ______________________________________                                         DAB9 is the abbreviation for Deutsches Arznei Buch (German Pharmaceutical     Handbook) 9th Edition.                                                   

                  TABLE 2                                                         ______________________________________                                        Change in the pH values in the stomach                                        on medication with dimethylpolysiloxane                                       Sub;. No 1      2      3    4    5    6    7    8                             ______________________________________                                        Before med.                                                                            1.80   1.96   1.92 1.98 1.51 2.11 6.03 1.69                          30 min   2.06   --     --   --   --   --   --   --                            after med.                                                                    2 hours  2.15   2.04   4.48 7.49 3.84 2.32 6.83 2.67                          after med.                                                                    No. of Tab.                                                                            2      4      4    2    2    2    4    2                             ______________________________________                                    

A positive influence on the pH by the medication is confirmed by thesign test (p<0.05, two-sided). However, no influence of the number oftablets on the increase in the pH can be established.

Subject 7 had a deformed duodenal cap due to scarring, without stenosis,was not included in the calculation because of the high pH values.

                  TABLE 3                                                         ______________________________________                                        Positive reaction on administration of                                        dimethylpolysiloxane chewable tablets                                         ______________________________________                                        2 dimethylpolysiloxane tablets                                                Subjects with                                                                 positive reaction* no reaction                                                                             n                                                ______________________________________                                        8                  0         8                                                ______________________________________                                        4 dimethylpolysiloxane tablets                                                Subjects with                                                                 positive reaction**                                                                              no reaction                                                                             n                                                ______________________________________                                        8                  0         8                                                ______________________________________                                         (*The reaction was minimal milky secretion in 5 of 8 subjects)                (**The reaction was minimal milky secretion in 1 of 8 subjects, otherwise     always a relatively large amount of milky secretion)                     

                  TABLE 4                                                         ______________________________________                                        Findings at the first investigation                                                        No. of                                                                  Time* tabl.   Finding                                                  ______________________________________                                        Subject No. 1                                                                          1       4       Signs of antral gastritis.                                                    Otherwise duodenum, stomach                                                   and oesophagus macroscopically                                                normal.                                              Subject No. 1                                                                          2       4       Gastric juice in the fundus;                                                  milky, cloudy and flocculent.                        Subject No. 1                                                                          3       4       Only minimal residues in the                                                  fundus. Otherwise empty as far                                                as the deep duodenum.                                Subject No. 2                                                                          1       2       Signs of slight antral                                                        gastritis. Otherwise duodenum,                                                stomach and oesophagus                                                        macroscopically normal.                              Subject No. 2                                                                          2       2       Gastric juice in the fundus;                                                  milky, cloudy and flocculent                         Subject No. 2                                                                          3       2       Still milky substance in the                                                  fundus. Duodenum and antrum                                                   empty.                                               Subject No. 3                                                                          1       2       Small hiatus hernia with                                                      reflux of grade 0-1. Otherwise                                                duodenum, stomach and                                                         oesophagus macroscopically                                                    normal.                                              Subject No. 3                                                                          2       2       Gastric juice in the fundus;                                                  milky, cloudy and flocculent                         Subject No. 3                                                                          3       2       Minute residues of milky,                                                     flocculent deposits. Fundus with                                              a film-like coating over large                                                areas. Duodenum empty.                               Subject No. 4                                                                          1       4       Duodenum, stomach and                                                         oesophagus macroscopically                                                    normal.                                              Subject No. 4                                                                          2       4       Gastric juice in the fundus;                                                  milky, cloudy and flocculent                         Subject No. 4                                                                          3       4       Slightly cloudy, milky gastric                                                juice. Otherwise duodenum,                                                    stomach, oesophagus normal.                          Subject No. 5                                                                          1       4       Small hiatus hernia with reflux                                               oesophagitis (grade 0-I).                                                     Otherwise duodenum, stomach                                                   and oesophagus macroscopically                                                normal.                                              Subject No. 5                                                                          2       4       Antrum with scabby-milky                                                      coating in the fundus. Very                                                   cloudy, milky fluid.                                 Subject No. 5                                                                          3       4       Residues of milky flakes in the                                               fundus. A few plaques in the                                                  antrum. Duodenum empty.                              Subject No. 6                                                                          1       4       Duodenum, stomach and                                                         oesophagus normal.                                   Subject No. 6                                                                          2       4       A few whitish, milky spots in the                                             antrum. Otherwise cloudy, milky                                               coating in the fundus.                               Subject No. 6                                                                          3       4       Very cloudy, milky fluid                                                      deposited on the fundus. A few                                                plaques in the antrum.                                                        Duodenum empty.                                      Subject No. 7                                                                          1       2       Deformed duodenal cap due to                                                  scarring, without stenosis.                                                   Stomach and oesophagus normal.                       Subject No. 7                                                                          2       2       Low-viscosity, milky deposits in                                              the fundus. Antrum, duodenum                                                  empty.                                               Subject No. 7                                                                          3       2       Minimal spots of milky deposits                                               in the stomach fundus. Otherwise                                              duodenum and antrum empty.                           Subject No. 8                                                                          1       2       Duodenum, stomach and                                                         oesophagus normal.                                   Subject No. 8                                                                          2       2       Low-viscosity but cloudy, milky                                               secretion in the fundus, film-like                                            coating. Antrum, duodenum                                                     empty.                                               Subject No. 8                                                                          3       2       Low-viscosity milky secretion as                                              film-like coating. Secretion                                                  cloudy. Antrum, duodenum                                                      empty.                                               ______________________________________                                         *Time 1 = immediately before medication                                       Time 2 = 1/2 hour after medication                                            Time 3 = 2 hours after medication                                        

                  TABLE 5                                                         ______________________________________                                        Findings at the second investigation                                          (after 7 days)                                                                             No. of                                                                  Time* Tabl.   Finding                                                  ______________________________________                                        Subject No. 1                                                                          1       2       Duodenum, stomach, oesophagus                                                 normal, distinct macroscopic                                                  improvement in antral gastritis.                                              pH 1.80                                              Subject No. 1                                                                          2       2       Distinctly less milky secretion                                               and film coating. Otherwise                                                   finding unchanged.                                                            pH 2.06                                              Subject No. 1                                                                          3       2       Minimal milky secretion in the                                                fundus. Duodenum, stomach                                                     normal.                                                                       pH 2.15                                              Subject No. 2                                                                          1       4       Continuing signs of slight antral                                             gastritis. Otherwise duodenum,                                                stomach and oesophagus normal.                                                pH 1.96                                              Subject No. 2                                                                          2       4       Large amount of high-viscosity                                                milky secretion in the fundus.                                                Otherwise antrum empty.                              Subject No. 2                                                                          3       4       Large amount of high-viscosity                                                milky secretion in the fundus.                                                Antrum, duodenum empty.                                                       pH 2.04                                              Subject No. 3                                                                          1       4       Small hiatus hernia with reflux of                                            grade 0- 1. Otherwise duodenum,                                               stomach and oesophagus                                                        macroscopically normal.                                                       pH 1.92                                              Subject No. 3                                                                          2       4       Large amount of high-viscosity                                                milky secretion in the antrum                                                 and fundus, duodenum empty.                          Subject No. 3                                                                          3       4       Large amount of residues of                                                   milky coating and secretion in                                                the antrum and fundus.                                                        Duodenum empty.                                                               pH 4.48                                              Subject No. 4                                                                          1       2       Duodenum, stomach and                                                         oesophagus macroscopically                                                    normal.                                                                       pH 1.98                                              Subject No. 4                                                                          2       2       Minimal milky secretion in the                                                fundus. Duodenum, antrum                                                      empty.                                               Subject No. 4                                                                          3       2       Only residues of cloudy, milky                                                secretion in the fundus.                                                      Duodenum and antrum otherwise                                                 empty.                                                                        pH 7.49                                              Subject No. 5                                                                          1       2       Small hiatus hernia with reflux                                               oesophagitis (grade 0-1).                                                     pH 1.51                                              Subject No. 5                                                                          2       2       Minimal milky secretion in the                                                corpus and in the antrum.                                                     Duodenum empty.                                      Subject No. 5                                                                          3       2       Little cloudy secretion in the                                                fundus. Antrum, duodenum                                                      empty.                                                                        pH 3.84                                              Subject No. 6                                                                          1       2       Duodenum, stomach and                                                         oesophagus normal.                                                            pH 2.11                                              Subject No. 6                                                                          2       2       Little milky, cloudy secretion in                                             the fundus and corpus.                               Subject No. 6                                                                          3       2       Minimal secretion in the                                                      duodenum and in the stomach.                                                  pH 2.32                                              Subject No. 7                                                                          1       4       Deformed duodenal cap due to                                                  scarring, without stenosis.                                                   Stomach and oesophagus normal.                                                pH 6.03                                              Subject No. 7                                                                          2       4       Little milky cloudy secretion in                                              the fundus. Antrum duodenum                                                   empty.                                               Subject No. 7                                                                          3       4       Minimal secretion in the fundus                                               without the milky cloudiness.                                                 Duodenum, antrum empty.                                                       pH 6.83                                              Subject No. 8                                                                          1       4       Duodenum, stomach and                                                         oesophagus normal.                                                            pH 1.69                                              Subject No. 8                                                                          2       4       Minimal, milky secretion as                                                   film-like coating. Tablets                                                    unchewed in the corpus.                                                       Duodenum empty.                                      Subject No. 8                                                                          3       4       Now large amount of cloudy,                                                   milky secretion as film-like                                                  coating in the fundus. Corpus,                                                duodenum, antrum empty.                                                       pH 2.67                                              ______________________________________                                         *Time 1 = immediately before medication                                       Time 2 = 1/2 hour after medication                                            Time 3 = 2 hours after medication                                        

                  TABLE 6                                                         ______________________________________                                        Summary of the findings in the dimethylpolysiloxane study                                          Frequency                                                               No. of                                                                              of occurrences                                                          subj. 2T    4T    t2  t3  t2 + 3                               ______________________________________                                        Signs of antral gastritis                                                                      2                                                            Antral gastritis macroscop.                                                                    1                                                            improved                                                                      Duodenum and antrum empty                                                                      6       6     4       4   6                                  Duodenum empty   3             3   1   2                                      Corpus empty     1             1       1                                      Minimal/little milky secretion                                                                 6       5     1   2   2   2                                  Minimal/residues of spots of                                                                   4       2     2   1   3                                      milky deposits                                                                A few plaques in the antrum                                                                    2       0     2   0   2                                      Milky, cloudy, flocculent                                                                      4       2     2   2       2                                  gastric juice                                                                 Milky deposits   5       3     2   2   1   2                                  Large amount of high-viscosity                                                                 3       0     3   1   1   1                                  milky secretion                                                               Large amount of residues of                                                                    1       0     1       1                                      milky coating and secretion                                                   ______________________________________                                         Abbreviations                                                                 No. of subj. = number of subjects;                                            T = tablets;                                                                  t = time                                                                 

                  TABLE 7                                                         ______________________________________                                        Findings in the dimethylpolysiloxane study                                                Subj.         No. of  Investigation                                           No.  Date     tabl.   time                                        ______________________________________                                        Signs of antral gastritis                                                                   1      March 15       1                                         Antral gastritis                                                                            1      March 22       1                                         macroscop. improved                                                           Signs of antral gastritis                                                                   2      March 15       1                                                       2      March 22       1                                         Small hiatus hernia                                                                         3      March 15       1                                                       3      March 22       1                                                       5      March 15       1                                                       5      March 22       1                                         Deformed duodenal cap                                                                       7      March 15       1                                         due to scarring,                                                                            7      March 22       1                                         without stenosis.                                                             Duodenum and antrum                                                                         2      March 15 2     3                                         empty         3      March 15 2     3                                                       4      March 22 2     2 and 3                                                 5      March 22 2     2 and 3                                                 7      March 15 2     2 and 3                                                 8      March 15 2     2 and 3                                                 2      March 22 4     2 and 3                                                 4      March 15 4     3                                                       7      March 22 4     2 and 3                                                 8      March 22 4     3                                         Duodenum empty                                                                              5      March 15 4     3                                                       6      March 15 4     3                                                       8      March 22 4     2                                         Corpus empty  8      March 22 4     3                                         Minimal milky secretion                                                                     8      March 22 4     2                                         (tablets unchewed in the                                                      corpus)                                                                       Minimal milky secretion                                                                     1      March 22 2     2 and 3                                   in the fundus 4      March 22 2     2 and 3                                                 5      March 22 2     3                                                       6      March 22 2     2                                         Minimal milky secretion                                                                     5      March 22 2     2                                         in the corpus and antrum                                                                    6      March 22 2     2                                         Fundus with minimal                                                                         7      March 15 2     3                                         spots of milky deposits                                                                     1      March 15 4     3                                         Little milky secretion in                                                                   7      March 22 4     2                                         the fundus                                                                    Stomach with minimal                                                                        7      March 15 2     3                                         spots of milky deposits                                                       Minimal secretion in the                                                                    6      March 22 2     3                                         duodenum and antrum                                                           Minimal secretion in the                                                                    7      March 22 4     3                                         fundus without milky                                                          cloudiness                                                                    A few whitish spots in                                                                      6      March 15 4     2                                         the antrum                                                                    Minute residues of                                                                          3      March 15 2     3                                         milky, flocculent                                                             deposits                                                                      Residues of milky flakes                                                                    5      March 15 4     3                                         in the fundus.                                                                A few plaques in the                                                                        5      March 15 4     3                                         antrum        6      March 15 4     3                                         Milky, cloudy,                                                                              2      March 15 2     2 and 3                                   flocculent gastric juice                                                                    3      March 15 2     2                                         in the fundus                                                                               1      March 15 4     2                                                       4      March 15 4     2 and 3                                   Low-viscosity, milky                                                                        7      March 15 2     2                                         deposits in the fundus                                                                      8      March 15 2     2 and 3                                   Fundus with film-like                                                                       3      March 15 2     3                                         coating over large area                                                       Antrum and fundus with                                                                      5      March 15 4     2                                         scabby-milky coating                                                          Fundus with cloudy,                                                                         6      March 15 4     2 and 3                                   milky coating                                                                 Large amount of high-                                                                       2      March 22 4     2 and 3                                   viscosity milky secretion                                                                   3      March 22 4     2                                         in the fundus                                                                 Large amount of high-                                                                       3      March 22 4     2                                         viscosity milky secretion                                                     in the antrum                                                                 Large amount of cloudy,                                                                     8      March 22 4     3                                         milky secretion as film-                                                      like coating in the                                                           fundus                                                                        Large amount of                                                                             3      March 22 4     3                                         residues of milky coating                                                     and secretion in the                                                          fundus.                                                                       Large amount of                                                                             3      March 22 4     3                                         residues of milky coating                                                     and secretion in the                                                          antrum                                                                        ______________________________________                                    

Dimethylpolysiloxane is obtained by hydrolysis and polycondensation ofdichlorodimethylsilane and chlorotrimethylsilane. The various typesdiffer in the nominal viscosity which is expressed by the number withthe substance name.

The degree of polymerization (n=20 to 400) is such that the kinematicviscosity ranges from 20 to 1,000 mm².s⁻¹ (20 to 1,000 cSt).

The structural formula of dimethylpolysiloxane is: ##STR1##

S 184 silicone antifoam agent from Wacker Chemie was used to prepare thechewable tablets in the tests described hereinbefore. Equivalent resultsare also achieved with dimethylpolysiloxane or silicone oils with akinematic viscosity in the range from 100 to 10,000 mm².s⁻¹, inparticular 300 to 3,000 mm².s⁻¹.

Aerosil 2000 was employed as highly disperse silica.

We claim:
 1. A method for treating gastritis in a patient in need ofsuch treatment, which comprises orally administering to the patient acomposition consisting essentially of a gastritis-treating effectiveamount of dimethylpolysiloxane with or without silica gel.
 2. The methodaccording to claim 1 wherein the dimethylpolysiloxane has a kinematicviscosity in the range of 100 to 10,000 mm².s⁻¹.